CN108135919A - For maintaining the composition of lactobacillus advantage - Google Patents

For maintaining the composition of lactobacillus advantage Download PDF

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Publication number
CN108135919A
CN108135919A CN201580083308.XA CN201580083308A CN108135919A CN 108135919 A CN108135919 A CN 108135919A CN 201580083308 A CN201580083308 A CN 201580083308A CN 108135919 A CN108135919 A CN 108135919A
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composition
acid
growth
single therapy
therapy agent
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Inventor
J·李
L·A·皮德
C·F·乔伊纳
R·A·冯萨
D·W·凯尼格
R·D·***
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Kimberly Clark Worldwide Inc
Kimberly Clark Corp
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Kimberly Clark Worldwide Inc
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/191—Carboxylic acids, e.g. valproic acid having two or more hydroxy groups, e.g. gluconic acid
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7016—Disaccharides, e.g. lactose, lactulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/719—Pullulans
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
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Abstract

The present invention provides be able to maintain that or promote certain Lactobacillus species bacterial strains growth composition and formulation.The composition and formulation usually contain only the single therapy agent selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2 deoxidation D ribose, 1 ketose and erlose.When being applied to user, the single therapy agent is unique bacterium carbon source.Although containing only single therapy agent, the composition has shown that the growth for promoting beneficial lactobacillus and maintenance and effectively inhibits the growth that relevant pathogen is infected with urogenital.Therefore, the application of the composition maintains healthy microbiologic population's balance in genito-urinary area.

Description

For maintaining the composition of lactobacillus advantage
Background technology
In the gastrointestinal tract of the mankind, on skin and other epithelium microenvironments (niche) and tissue microenvironment (such as oral cavity, Ocular and vagina) in be colonized with microorganism.In healthy human body, single part or organization type may live it is hundreds of not Congener bacterium.Phase interaction between various bacteria cultures in these bacterial communities and between bacterium and human host With, using the resource for the distribution for influencing various bacteria cultures availability and competitive structure of community is moulded.Such money Source may be the availability that food, geographical location and growing space or bacterium may adhere to physical arrangement thereon.
Health microbiologic population provide a variety of benefits for host, including broad spectrum of pathogens is colonized resistance, biology conjunction Into with nutriment necessary to absorption and immunostimulation.For example, normal vagina usually contains in every milliliter of vaginal fluid Have more than about 104A lactobacillus (1actobacilli).Under normal circumstances, vaginal flora provides weak acid environment, so as to Help to resist the invasion of pathogenic microorganism.But unfortunately, this vagina balance may be easy to be eventually led to vagina sense A variety of foeign elements of dye are broken.Vagina infection is a kind of clinical syndrome, is existed with three kinds of principal modes, i.e. bacterial vaginosis Scorching, monilial vaginitis (" colpomycosis ") and trichomonas vaginitis (" trichomoniasis ").
Scheme currently used for treating vaginal bacterial infection is related to using various broad-spectrum antibiotics, such as metronidazole.However, Antibiotic is often undesirable, because they may kill the extensive normal bacteria group of intravaginal, including beneficial newborn bar Bacterium.This may cause secondary complication, the reason is that lactobacillus has restraining function to the various chance pathogens of intravaginal.So Treatment is likely to require further treatment scheme afterwards, such as takes in the dairy products through culture to substitute internal lactobacillus, with And utilize antifungal therapies.Anaerobic bacteria level is caused to increase further, since lacking lactobacillus, this may be such that infection becomes more It is complicated.In addition, when intravaginal frequently uses antibiotic, antibiotic may be by causing general toxicity from vaginal absorption.
Therefore, the improved combination in a healthy and balanced way for supporting and safeguarding microbiologic population in genito-urinary area is needed at present Object, the composition more specifically improved.
Invention content
It has now surprisingly been found that the growth of certain lactobacillus strains can by application comprising selected from isomaltoketose, Maltitol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose single therapy The pharmaceutical composition of agent and increase.In certain embodiment kinds, the growth increased beneficial to lactobacillus can effectively inhibit and uropoiesis The growth of the associated pathogen of genital infection, and help to safeguard the in a healthy and balanced way of microbiologic population in genito-urinary area. Therefore, the composition comprising single therapy agent is very suitable for being locally applied to the genito-urinary area of women, is secreted with supporting and safeguarding Microbiologic population is in a healthy and balanced way in regio urogenitalis.For example, provide include selected from isomaltoketose, maltitol, amylopectin, Maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose the composition of single therapy agent promote newborn bar The growth of bacterium is without promoting pathogenetic bacteria such as Escherichia coli (Escherichia coli) or gardnerella vaginalis The growth of (Gardnerella vaginalis).
Therefore, in certain embodiments, the present invention provides a kind of compositions, and it includes selected from isomaltoketose, wheat Bud sugar alcohol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose single therapy Agent, wherein the therapeutic agent promotes the growth of lactobacillus.In particularly preferred embodiments, the application of pharmaceutical composition is not only Promote the growth of lactobacillus, and also result in the inhibition of enteropathic bacteria such as gardnerella vaginalis.
In other embodiments, the present invention provides a kind of pharmaceutical compositions, and it includes selected from isomaltoketose, malt The single therapy agent of sugar alcohol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose, Wherein described single therapy agent accounts for about 0.05 to about 1.0 weight/volume %, wherein pharmaceutical composition is administered in need make User promotes the growth of lactobacillus.
In other embodiments, the pharmaceutical composition of the present invention can be configured to applying for user in need Formulation.Suitable formulation can include such as liquid, solution, paste or gel.Therefore, in a preferred implementation In scheme, the present invention provides the formulations for local application to user, and it includes selected from isomaltoketose, maltose Alcohol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose single therapy agent peace treaty At least one gelling agent including gellan gum of 0.05 to about 5.0 weight/volume %.In particularly preferred embodiments, it is single One therapeutic agent accounts for about 0.1 to about 2.0 weight/volume %, and the pH of formulation is about 3.5 to about 5.5.
In also having other embodiments, composition of the invention can be applied to application device.Suitable application device Including web, such as wet-laying thin paper net or air-laid fibre web, gauze, cotton swab, percutaneous plaster, container or holding Device.Therefore, in certain embodiments, the composition can be applied to non-woven webs, such as meltblown fiber web, It spins (coform) web, spun-bonded fibre net, air-laid fibre web, Hydroentangled non-woven webs, spun lacing web, glue Close carding fiber net and the laminates and wet-laid fibrous web of these webs, such as thin paper net.
In other respects, composition of the invention can be administered to user to provide therapeutic effect.Therefore, at one In embodiment, the present invention provides for enhance in vivo lactobacillus growth or activity method, include using comprising Selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and glucopyranose The composition of the single therapy agent of base sucrose.
Definition
As used herein, term " inhibition ", which is generally meant that, reduces measurable amount or entirely prevents.
As used herein, term " urogenital system " refers to vulva, vagina, the urinary tract, bladder and peripheral region.
As used herein, term " effective quantity " and " therapeutic dose " are to be enough to inactivate the pathogenic microorganism for leading to vagina infection But the amount not necessarily killed.In fact, although being not required, dense with inhibition concentration, non-cell toxicity concentration or clinic Degree is in use, may be expected to use the growth characteristics that do not significantly affect or inhibits normal vagina flora or otherwise notable Stimulate the concentration of vagina tissue.For example, it is desirable to the concentration of about 0.01 to about 5.0 weight/volume % using single therapy agent, it should Concentration is about 0.1 to about 2.0 weight/volume % in some embodiments, is about 0.2 to about 1.5 in some embodiments Weight/volume %, and it is in some embodiments about 0.5 to about 1.0 weight/volume %.It should be appreciated that dosage can be with year The type for the infection that age, the state of an illness and patient are subjected to and change, and can easily be determined by those skilled in the art.
As used herein, term " therapeutic effect " refers to composition of the invention and formulation relative to Escherichia coli (E.coli) stimulation Lactobacillus crispatus (L.crispatus)) growth ability, which is according to therapeutic effect described below What scheme measured.Therapeutic effect is typically expressed as the ratio of Lactobacillus crispatus and Escherichia coli, and is desirably larger than about 30, more Preferably more than about 50 and more desirably greater than about 100.
As used herein, title " weight/volume % " or " weight/volume " refer to the weight (in gram) of substance divided by The volume (in terms of milliliter) of solution is multiplied by with 100 obtained values.
As used herein, when mentioning pentose, disaccharides, organic acid, cyclodextrin, pectin substance or indigestible polysaccharide, art Language " solvable " means the substance according to L.Prosky et al., J.Assoc.Off.Anal.Chem.71,1017-1023 (1988) Described method is at least soluble.
Specific embodiment
The composition and formulation of the present invention is intended to stimulate the Gram-positive for belonging to Lactobacillus species bacillar Growth.It is believed that by reducing or excluding pathogenetic bacteria group, the growth and advantage that stimulate lactobacillus will re-establish health Flora.The composition of the present invention usually contains only single therapy agent, can promote the Gram-positive for belonging to Lactobacillus species Bacillar growth.Preferably, the single therapy agent is selected from isomaltoketose, maltitol, amylopectin, malt three Sugar, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose.
The composition spy and formulation of the present invention is not suitble to be applied to urogenital tract to support micro- life of simultaneously maintaining healthy Object group.In other embodiments, composition of the invention and formulation can be used for supporting and safeguard on skin, bladder or Microbiologic population in gastrointestinal tract it is in a healthy and balanced way.For example, safeguard and support that the microbiologic population of health can be by that will combine Object is locally applied to other regions of urogenital tract or body to realize.In other embodiments, composition of the invention It can be formulated for being administered orally, then be administered orally to patient to support and safeguard the healthy microbiologic population in gastrointestinal tract.
In general, therapeutic combination contain only selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2- deoxidations- The single therapy agent of D-ribose, 1-kine trisaccharide and erlose.The composition can include other components, such as Stabilizer, surfactant, solubilizer, buffer, suspending agent, colorant, pH adjusting agent, tackifier, dispersant, preservative or Solvent, but usually contain only a kind of therapeutic agent for being capable of providing therapeutic effect.
The urogenital system therapeutic combination of the present invention usually stimulates health, natural bacterium such as Lactobacillus species Growth, and user can be administered to by several forms.For example, urogenital system composition can be prepared into preparation Object is administered to user or can be applied to base material (such as wipe substrate) to be administered to user.It preferably, can be at this The sugar used in invention is soluble, its formulation to be facilitated to be administered to user.
, it is surprising that comprising selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2- deoxidations-D- The composition of the single therapy agent of ribose, 1-kine trisaccharide and erlose promotes healthy bacterium such as Lactobacillus species And the more particularly growth of lactobacillus acidophilus (Lactobacillus acidophilus), without promoting enteropathic bacteria Such as Gardnerella (such as gardnerella vaginalis), candida albicans (Candida) (such as Candida albicans (Candida )) and/or the life of trichmonad (Trichomonas) (such as trichomonas vaginalis (Trichomonas vaginalis)) albicans It is long.Therefore, composition of the invention can be applied to user selectively to stimulate the growth of lactobacillus without stimulating emulation The growth of property enteropathic bacteria.Therefore, in use, using comprising selected from isomaltoketose, maltitol, amylopectin, Maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose the formulation of single therapy agent can enhance It the growth in user of healthy bacterium such as Lactobacillus species and colonizes, so as to help to reduce the generation of disease.
Therefore, in preferred embodiments, comprising selected from isomaltoketose, maltitol, amylopectin, malt three Sugar, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose the composition of single therapy agent realize Lactobacillus crispatus Growth better than Escherichia coli, as measured by the following therapeutic effect schemes of use.Preferably, it is obtained using the composition The ratio of Lactobacillus crispatus and Escherichia coli be greater than about 30, be still more preferably greater than about 50, be still more preferably more than 100 and Even more preferably greater than about 300.
In general, the composition that can be used in the present invention contains only single therapy agent.Therapeutic agent generally comprises sugar.For example, In one embodiment, composition can include pentose, more preferable 2-deoxy-D-ribose.In other embodiments, it is single to control It can be sugar alcohol to treat agent, more preferable maltitol, with formula C12H24O11.In other other embodiments, single therapy agent Can be disaccharides, more preferable isomaltoketose, by glucose and fructose by α -1,6- glucosides key connections form.In addition its In his embodiment, single therapy agent can be polysaccharide, more preferable amylopectin, be made of maltotriose unit and then With general formula (C6H12O5)n.In other other embodiments, single therapy agent can be trisaccharide, such as maltotriose, 1- sugarcanes Fruit trisaccharide and erlose.
Preferably, the composition contains only single therapy agent.That is, composition usually contains only one kind selected from different malt ketone The treatment of sugar, maltitol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose Agent.It is known as the carbon source of gram-positive bacteria and other medicaments with therapeutic effect such as glucose, fructose, galactolipin, sweet Dew sugar, lactose, lactulose, trehalose, cellobiose, melibiose, melitriose, dextrin, starch and glycogen are not the groups of the present invention Point., it is surprising that the composition for containing only single therapy agent has been demonstrated that the growth of lactobacillus and position health can be stimulated Flora and without addition second carbon source.Therefore, composition of the invention usually contain only can be utilized by Gram-negative bacteria it is single Carbon source, further, it is preferred that the single carbon source be selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2- deoxidations- D-ribose, 1-kine trisaccharide and erlose.
The composition of the present invention generally comprises the therapeutic agent of less than about 10.0 weight/volume %.In particularly preferred implementation In scheme, the total amount of therapeutic agent is less than about 5.0 weight/volume %, and still more preferably less than about 2.5 weight/volume %, all Such as from about 0.01 to about 2.0 weight/volume % and more preferably about 0.1 to about 1.5 weight/volume %.For example, in a reality Apply in scheme, composition include about 0.1 to about 2.0 weight/volume % selected from isomaltoketose, maltitol, amylopectin, The single therapy agent of maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose.
In addition, the first therapeutic agent and second therapeutic agent should be to be enough to provide response to treatment when being administered to user Amount provide.For example, when composition is included selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2- deoxidations-D- During the single therapy agent of ribose, 1-kine trisaccharide and erlose, the single therapy agent is to be enough to stimulate certain health Bacterium such as lactobacillus bulgaricus (Lactobacillus bulgaricus), lactobacillus acidophilus, lactobacillus gasseri (Lactobacillus gasseri), Lactobacillus crispatus, Lactobacillus casei (Lactobacillus casei), lactobacillus plantarum The amount of the growth of (Lactobacillus plantarum) exists.Preferably, the composition provides greater than about 30, more preferably Greater than about 100,200 and even more preferably greater than about 300 therapeutic effect, the Test Methods section of following article are more preferably greater than about Described in, with Lactobacillus crispatus and the ratio measures of Escherichia coli.
The composition of the present invention can be prepared for being administered to user.It is controlled for example, being formulated into vagina in composition In those embodiments for treating formulation, it can be formulated into：Spraying, moisturizer, lotion, creme, jelly, liniment, cream Agent, ointment, oil, foam, gel, film, irrigation, suppository, release polymer, coating, liquid, vaginal capsule, vaginal tablet, the moon Road film, vaginal sponge, vagina ovule etc..The composition can also be previously applied to vaginal inset, tampon, cleaning piece or cushion, Then it is applied to vagina again.Formulation can be taken off selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2- The single therapy agent of oxygen-D-ribose, 1-kine trisaccharide and erlose and solvent and optional dermatology are subjected to Carrier.As used herein, " the acceptable carrier of dermatology " typically refer to be suitble to be locally applied to collenchyme and with The compatible carrier of prebiotics.The acceptable carrier of dermatology can be various forms, such as simple solution (it is water base or Oil base), solid form (such as gel or club) and emulsion.
Solvent can be aqueous or non-aqueous.Water is particularly preferred aqueous solvent.Non-aqueous solvent can include Such as glycols, such as propylene glycol, butanediol, triethylene glycol, hexylene glycol, polyethylene glycol, ethoxydiglycol and dipropylene glycol； Alcohols, such as ethyl alcohol, normal propyl alcohol and isopropanol；Triglycerides；Ethyl acetate；Acetone；Glyceryl triacetate；And their group It closes.In general, solvent percentage is greater than about 75 weight/volume %, more preferably more than about 85 weight/volume % and goes back More preferably more than about 90 weight/volume %.
The composition of the present invention is typically acid, i.e. pH is less than about 7.0 and more preferably less than about 6.0, such as about 3.0 to about 6.0 and more preferably about 4.0 to about 5.0.In an especially preferred embodiment, pH can be maintained at Faintly acid is horizontal, to correspond to normal vaginal environment.For example, pH can be in the range of about 3.0 to about 6.0, in some realities It applies in scheme in the range of about 3.5 to about 5.0, and in some embodiments in the range of about 4.0 to about 4.5.It is aforementioned Acid ph value can also provide other benefits.For example, when the composition is configured to form gel, it is all as described below, it is low PH levels can also improve gelation rate and gel strength, to reduce after the composition is inserted into vagina with regard to leaking Possibility.
The pH of composition can be adjusted using organic acid.The organic acid that can be used in the present invention is usually by having one At least one of monocarboxylic acid or the polycarboxylic acids composition of a or multiple hydroxy functional groups, described hydroxy functional group are introduced in alpha-position In (that is, on the carbon atom of neighbouring carboxyl functional group).The example of particularly useful organic acid includes citric acid, lactic acid, methyl breast Acid, phenyl-lactic acid, malic acid, mandelic acid, glycolic, hydroxymalonic acid, tartaric acid and gluconic acid.In particularly preferred embodiment party In case, organic acid is selected from citric acid, lactic acid, malic acid, glycolic and tartaric acid.In certain embodiments, can be organic Acid provides appropriate counter ion counterionsl gegenions, such as calcium, sodium or magnesium.In particularly preferred embodiments, composition may include selected from different Maltulose, maltitol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose Single therapy agent and organic acid.In other embodiments, composition may include selected from isomaltoketose, maltitol, branch Chain starch, maltotriose, 2-deoxy-D-ribose, the single therapy agent of 1-kine trisaccharide and erlose and selected from lemon Lemon acid, lactic acid, malic acid, glycolic and tartaric acid organic acid.
In view of foregoing teachings, in certain embodiments, composition of the invention and formulation can have about 3.0 to about 6.0, the pH of more preferably from about 3.5 to about 5.0, and comprising selected from isomaltoketose, maltitol, amylopectin, maltotriose, The single therapy agent of 2-deoxy-D-ribose, 1-kine trisaccharide and erlose, the total amount of wherein therapeutic agent is about 0.1 To about 2.0 weight/volume %.
The present invention a particular embodiment in, for example, the composition be configured as it is rapid when being applied to vagina Form gel." gel " is a kind of colloid, and wherein dispersed phase is combined to generate gelatin, solid-state or semisolid with decentralized medium Material.Gel can be formed in less than about one hour, be formed in less than about one minute in some embodiments, and It is formed in less than about 30 seconds in some embodiments.Inter alia, this fast gelation effect reduces validity period Between the possibility that leaks.In addition, since gel can be formed in intravaginal, so more likely being kept within the extended period Its structure and shape.The long-acting of therapeutic agent that is used to inhibit and/or treat vagina infection is released in this way, gel can provide It puts.For example, gel can be retained in intravaginal about 2 to about 48 hours, to provide desired effect.
Although multiple compounds can be used, usually using water as the decentralized medium of gel to optimize bio-compatible Property.Other possible decentralized media include non-aqueous solvent, including glycols, such as propylene glycol, butanediol, triethylene glycol, oneself Glycol, polyethylene glycol, ethoxydiglycol and dipropylene glycol；Alcohols, such as ethyl alcohol, normal propyl alcohol and isopropanol；Triglycerides；Second Acetoacetic ester；Acetone；Glyceryl triacetate；And combination thereof.In general, decentralized medium (such as water) is shared in the composition Percentage is greater than about 75 weight/volume %, in some embodiments greater than about 90 weight/volume %, and in some implementations It is about 95 to about 99 weight/volume % in scheme.
The dispersed phase of gel can be formed by any one of a variety of different gelling agents, including temperature-responsive (" hot glue It is solidifying ") compound, ion responsitivity compound etc..For example, hot gelling system by being transformed into gel from liquid, becomes temperature Change (such as temperature raising) to make a response.In general, interested temperature range is about 25 DEG C to about 40 DEG C, in some implementations It is about 35 DEG C to about 39 DEG C in scheme, and is human body temperature (about 37 DEG C) in one particular embodiment.It is attached in the temperature It is useful to change the composition of state near temperature, because they will be retained in body cavity, such as is being delivered it Afterwards.The a variety of thermal gelations that can be gelled when being applied to vagina close any one of object and can be used in the present invention.One In the case of a little, block copolymer, graft copolymer and/or homopolymer can be coagulated using hot glue.For example, polyoxyalkylene block copolymer Object can be used for forming thermo-gelling composition in some embodiments of the present invention.Suitable thermo-gelling composition can include Such as homopolymer, such as poly- (N- methyl-N-n-propyls acrylamide), poly- (N- propyl Methacrylamides), poly- (N- methyl-N- N-isopropylacrylamide), poly- (N- n-propyls Methacrylamide), poly(N-isopropylacrylamide), poly- (N, N- diethyl third Acrylamide)；Poly- (N- isopropyl acrylamides), poly- (N- cyclopropyl acrylamide), poly- (N- ethyl methacrylamides), It is poly- (N- methyl-N-ethylacrylamides), poly- (N- Cvclopropvlmethvls acrylamide) and poly- (N- ethyl acrylamides).Suitably Other other examples of thermogelling polymers can include cellulose ether derivative, such as hydroxypropyl cellulose, methylcellulose, Hydroxypropyl methyl cellulose and ethylhydroxyethylcellulose.In addition, thermogelling polymers can be made in the following manner：It prepares The copolymer of two or more monomer or by such homopolymer and other water-soluble polymers such as acrylic monomers (for example, acrylic or methacrylic acid, acrylate or methacrylate, acrylamide or Methacrylamide and it Derivative) mixing.
The composition of the present invention can also include ion responsitivity compound.Such compound is typically crowd in the art Well known, and tend to form gel in the presence of certain ions or under some pH.For example, it can make in the present invention A kind of suitable ion responsitivity compound is anion polysaccharide.Anion polysaccharide can form Space network of polymer, For serving as the dispersed phase of gel.In general, anion polysaccharide include the polysaccharide with total anionic charge and containing the moon from The neutral polysaccharide of sub- functional group.
Any one of a variety of anion polysaccharides that gel can be formed when being contacted with vagina mucosa can be in the present invention Middle use.It is such to be formed under anion polysaccharide normal acidic pH value present in vagina (for example, about 2.5 to about 5.5) of gel Typically stablize.For example, formed gel anion polysaccharide some suitable examples include natural gum, such as gellan gum and Alginate glue (such as ammonium salt and alkali metal salt of alginic acid)；Chitosan；Carboxymethyl cellulose, pectin, carrageenan, xanthan Glue and their derivative or salt.The composition and its will partly depend on to the selection of certain types of anion polysaccharide Used in other compositions property.For example, carrageenan is to certain types of cation sensitive, for example, it is usually in potassium Rather than it is gelled in the presence of sodium.Similarly, uronic acid glycan (Glycuronan) is usually at bivalent cation (such as Ca2+) Rather than it is gelled in the presence of monovalent cation (such as Na+).Xanthans can be gelled in the presence of bivalent cation, but only It is gelled under relatively high pH.
Although any one of above-mentioned anion polysaccharide can be used in the present invention, it is cold that knot is used in the present invention Glue (no matter be single use or be used in combination with other gelling agents) is especially desirable, the reason is that gellan gum can be more Gel is formed in the presence of kind various different cationic (not only including univalent cations but also including bivalent cation).Gellan gum purport Covering any type of gellan gum, including natural gellan gum, clarification gellan gum, deacylation gellan gum, on-acylated gellan gum (example Such as, generated by the bacterium be transformed through genetic engineering), (this polysaccharide completely or partially takes off clarification gellan gum from bacterial debris Except), chemical modification gellan gum etc..Various types of gellan gums and the method for gellan gum is used to form in U.S. Patent number 4,326, 052nd, it is described in 4,326,053,4,377,636,4,385,123 and 4,563,366.Suitable gellan gum can from it is a variety of not Same source is commercially available.For example, GELRITETM gellan gums are available from Sigma-Aldrich Chemical Co. (St.Louis, MO), be by naturally occurring polysaccharide through deacylation and clarifying treatment prepared by.Deacylation gellan gum also can be from CP Kelco U.S., Inc. (Chicago, IL) are with titleIt obtains.
Gellan gum can be high acyl gellan gum or low-acyl gellan gum.In high acyl group (or " natural ") form, exist Two acyl substituents, i.e. acetic acid esters and monoglyceride.The two substituent groups are located on same glucose residue, average next It says, there are one acetic acid esters there are one monoglyceride, each two repetitive unit for each repetitive unit.In low acyl form, acyl group It can completely or partially be removed by deacylation.The deacylation degree of deacylation gellan gum can be at least about 20%, one It is at least about 50% in a little embodiments, and is at least about 75% in some embodiments.Alternatively, low acyl group knot is cold Glue can be the gellan gum of " on-acylated ", because this gellan gum is without using acyl group by the bacterium being transformed through genetic engineering In the case of formed.No matter low-acyl gellan gum is formed in which way, and gelation temperature is usually all in 30 to 50 DEG C of model In enclosing, it is possible that be particularly suitable for being used in the present invention, in this way, low-acyl gellan gum can under about 37 DEG C of body temperature glue It is solidifying, and keep stablizing at a temperature of about 25 DEG C of typical storage and transportation.In addition, low-acyl gellan gum or firm flexible, so as to Its shape can be kept after vaginal canal is delivered to.
In most of embodiments, the amount of one or more gelling agents in the composition is about 0.01 to about 10.0 weight/volume % are about 0.05 to about 5.0 weight/volume % in some embodiments, and in some embodiments In be about 0.1 to about 1.0 weight/volume %.
If desired, cementitious compositions can be provided by any desired form (such as liquid, powder etc.).In fact, The special benefit of one of the composition is that it can be used as liquid application, this just allows selection than can be used for solid-state or half originally The wider array of application technique of application technique category of solid gel.A kind of technology that may be used includes filling by liquid application It puts (such as syringe or pipe) the composition is assigned in vaginal canal.The applied volume of the composition may be constructed single agent Amount or two or more times dosage.Although being not required, the composition can also sterilize before administration.Sterilizing It can be completed by any technology known in the art, such as using gas (such as ethylene oxide), radiation (such as γ spokes Penetrate) or it is hot (high pressure sterilization).If desired, the composition can be subjected to one or more filtration steps before sterilizing, with side Help removal pollutant.
The composition of the present invention can be applied in suitable base material, the base material and then can be used for therapeutic agent being applied to User.Suitable application device includes web, such as wet-laying thin paper net or air-laid fibre web, gauze, cotton swab Son, percutaneous plaster, container or retainer.Particularly preferred application device includes web, including flushable and not flushable The non-woven webs of cellulose net and composite fibre materials.Available web can be wet-laid fibrous web, air-flow Networking web, meltblown fiber web or spun-bonded fibre net.Suitable composite fibre materials include melt-blown polyethylene, polypropylene, gather Ethylene and polyacrylic copolymer include polyethylene or polyacrylic bicomponent fibre etc..Available non-woven webs can be with It is meltblown fiber web, spinning web, spun-bonded fibre net, air-laid fibre web, Hydroentangled non-woven webs, spun lacing fibre Tie up net, bonded carded fibrous web.
In certain embodiments, particularly composition is applied in those embodiments of web, it may be desirable to Be that formulation provides certain physical attributes, such as with smooth, lubrication, the texture of non-greasy；It can be at least partly from fibre Dimension net is transferred on the skin of user；It can be retained on web at around room temperature；It or can be with web manufacture Process compatible.Make in certain embodiments, it is preferred that at least part of the composition is transferred to when in use from thin paper On the skin of user.
The composition can be applied to during web is formed or after web has been formed and is dried Web, latter situation are frequently referred to processed offline or post processing.The composition is applied to the suitable method packet of web Include methods known in the art, such as intaglio printing, flexographic printing, spraying, WEKOTM, slit coating or electrostatic spraying.One The particularly preferred offline applying method of kind is rotogravure printing.
Test method
Therapeutic effect scheme
The following bacterium colony for being prepared for both bacteriums of Lactobacillus crispatus and Escherichia coli.By the colony lift of Lactobacillus crispatus Into 7ml MRS meat soups, under 37 DEG C of anaerobic conditions (using the BD GasPak EZ anaerobic bacterias containment system with indicator) It incubates 18 to 20 hours, during which nonoscillatory.By in the colony lift of Escherichia coli to 5ml TSB meat soups, in 37 DEG C of aerobic item (being vibrated with 100rpm) incubates 18 to 20 hours under part.
Then it is inoculated with bacterium colony as follows.Gently be vortexed bacterial cultures, and 1mL is then taken out from each culture is transferred to pair In the 2.0mL microcentrifugal tubes answered, centrifuged two minutes with 14,500rpm.Culture supernatants are removed, cell precipitate is resuspended In 1mL 0.95% (weight/volume %) brine.Then the bacterium colony of resuspension is centrifuged two minutes with 14,500rpm, in removing Clear liquid.For Lactobacillus crispatus, sediment is resuspended in 0.95% brine of 1mL, reaches about 107To 108cfu/mL.For Sediment is resuspended in 0.95% brine of 1mL by Escherichia coli, reaches about 108To 109cfu/mL。
Prepare culture medium as follows.
Table 1
All dispensings in mixture table 1, and pH is adjusted to 6.5.Then culture medium high pressure sterilization 20 is divided at 125 DEG C Clock.In order to assess the effect of various sugar and organic acid (being denoted as carbon source below), it is prepared for following sample：
Table 2
It takes out five milliliters (5mL) from each culture medium to be transferred in test tube, in duplicate, for subsequent inoculations.With 1, 000: 1 ratiometric is for Lactobacillus crispatus and the main mixture of Escherichia coli (the two is prepared as described above).With the main mixing Object is inoculated with every (5ml) test tube, amounts to 10 so as to have in every test tube5To 106The Lactobacillus crispatus of a CFU and altogether 100 to The Escherichia coli of 1,000 CFU.
To establish negative control, a test tube is vortexed and takes out 100 μ L, (often to be diluted by serial dilution and bed board Once 2 plates of paving) determine initial cell density.It is selected on the MRS agar plates for incubating two days under 37 DEG C of anaerobic condition Select Lactobacillus crispatus.Escherichia coli are selected on the TSA tablets for incubating one day under 37 DEG C of aerobic conditions.By coculture It is placed in the anaerobism container with BD GasPaks, is incubated 36 hours at 37 DEG C.
Influence of the carbon source to the ratio of Lactobacillus crispatus and Escherichia coli is measured within 36 hours after inoculation.Test tube will be co-cultured It is vortexed and takes out 100 μ L, to determine final cell concentration by serial dilution and bed board (often dilution once spreads 2 plates). It is incubated under 37 DEG C of anaerobic condition and selects Lactobacillus crispatus on the MRS agar plates of two days.In 37 DEG C of aerobic conditions Escherichia coli are selected on the lower TSA tablets for incubating one day.
Embodiment
The sample of the present invention is prepared by adding carbon source as shown in table 3 below.Then it uses above in test method portion Measuring method described in point measures the therapeutic effect of formulation.Therapeutic effect is summarised as Lactobacillus crispatus and large intestine bar below The ratio of bacterium.
Table 3
In view of above description and examples, the present invention provides a kind of pharmaceutical composition in the first embodiment, Comprising selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and pyrans The single therapy agent of glucityl sucrose and aqueous solvent.
The present invention further provides first embodiment with the pH less than about 5.0 in second embodiment Composition.
In addition, the present invention provides the combination of first embodiment or second embodiment in the third embodiment Object, wherein therapeutic agent account for about 0.1 to about 2.0 weight/volume %.
The present invention also the 4th embodiment, provides first embodiment to third embodiment in it is any The composition of person, wherein the composition promote growth of the Lactobacillus crispatus relative to Escherichia coli so that therapeutic effect is greater than about 30.In other other embodiments, therapeutic effect can be greater than about 100, and also more preferably more than about 200, for example, about 200 To about 600.
The present invention is further provided in the 5th embodiment in first embodiment to the 4th embodiment The composition of any one, wherein lactobacillus growth or active sole carbon source are single therapy agent for promoting in vivo. In such embodiment, it is preferred that composition be free of as glucose, fructose, galactolipin, mannose, lactose, lactulose, Trehalose, cellobiose, melibiose, melitriose, dextrin, starch or glycogen.
The composition of any one can be configured to liquid, paste or gel in first to the 5th embodiment, should Liquid, paste or gel have the pH of about 3.0 to about 5.0, and include the therapeutic agent of about 0.1 to about 2.0 weight/volume %.
The present invention is bacillary caused by also being used to treat gardnerella vaginalis embodiment, provides one kind at the 6th The method of vaginitis, this method include appointing into first to the 5th embodiment of vagina local application of women in need The composition of one.
In yet another embodiment, the present invention provides a kind of for enhancing the in vivo growth of lactobacillus or activity Method, including applying the composition of any one in first embodiment to the 5th embodiment to patient in need.

Claims (20)

1. a kind of pharmaceutical composition, it includes selected from isomaltoketose, maltitol, amylopectin, maltotriose, 2- deoxidations- The single therapy agent of D-ribose, 1-kine trisaccharide and erlose and aqueous solvent.
2. composition according to claim 1, wherein the single therapy agent accounts for about the 0.1 to about 2.0 of the composition Weight/volume %.
3. composition according to claim 1, wherein the pH value of the composition is about 3.0 to about 5.0.
4. composition according to claim 1, wherein the composition promotes Lactobacillus crispatus relative to Escherichia coli Growth so that therapeutic effect is greater than about 30.
5. composition according to claim 1 is also included selected from citric acid, lactic acid, methyllactic acid, phenyl-lactic acid, apple Tartaric acid, mandelic acid, glycolic, hydroxymalonic acid, tartaric acid and gluconic acid organic acid, the composition has about 3.0 to about 5.0 PH, and wherein the composition promotes growth of the Lactobacillus crispatus relative to Escherichia coli so that therapeutic effect is greater than about 100。
6. composition according to claim 5, wherein the single therapy agent accounts for about the 0.5 to about 1.5 of the composition Weight/volume %.
7. a kind of pharmaceutical formulation being used for user's local application in need, it includes selected from isomaltoketose, malt The single therapy agent of sugar alcohol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose, Solvent and gelling agent.
8. pharmaceutical formulation according to claim 7, wherein the single therapy agent accounts for about 0.1 to about 2.0 weight/body Product %.
9. pharmaceutical formulation according to claim 7, wherein the pH of the composition is about 3.0 to about 5.0.
10. pharmaceutical formulation according to claim 7, wherein the composition promotes Lactobacillus crispatus relative to large intestine bar The growth of bacterium so that therapeutic effect is greater than about 30.
11. pharmaceutical formulation according to claim 7, wherein the composition promotes Lactobacillus crispatus relative to large intestine bar The growth of bacterium so that therapeutic effect is greater than about 100.
12. it is a kind of for maintaining the method for the healthy microbiologic population balance in the genito-urinary area of patient in need, it is described Method includes the genito-urinary area topical composition to the patient, and the composition is included selected from isomaltoketose, wheat Bud sugar alcohol, amylopectin, maltotriose, 2-deoxy-D-ribose, 1-kine trisaccharide and erlose single therapy Agent and aqueous solvent.
13. according to the method for claim 12, wherein the single therapy agent accounts for about the 0.1 to about 2.0 of the composition Weight/volume %.
14. according to the method for claim 12, wherein the composition has the pH of about 3.0 to about 5.0.
15. according to the method for claim 12, wherein the application of the composition maintains the pH of the genito-urinary area In the range of about 3.5 to about 4.5.
16. according to the method for claim 12, wherein the composition promotes Lactobacillus crispatus relative to Escherichia coli Growth so that therapeutic effect is greater than about 30.
17. according to the method for claim 12, wherein the composition promotes Lactobacillus crispatus relative to Escherichia coli Growth so that therapeutic effect is greater than about 100.
18. according to the method for claim 12, wherein applying said compositions increase the growth of in vivo lactobacillus Or activity.
19. according to the method for claim 12, wherein the single therapy agent be to the patient apply it is unique carefully Bacterium carbon source.
20. according to the method for claim 12, wherein the composition also include selected from citric acid, lactic acid, methyllactic acid, Phenyl-lactic acid, malic acid, mandelic acid, glycolic, hydroxymalonic acid, tartaric acid and gluconic acid organic acid, the composition has The pH of about 3.0 to about 5.0, and wherein described composition promotes growth of the Lactobacillus crispatus relative to Escherichia coli so that it controls Therapeutic effect is greater than about 100.
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